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Abstract

Introduction

Esophageal Doppler was confirmed as a useful non-invasive tool for management of fluid
replacement in elective surgery. The aim of this study was to assess the effect of
early optimization of intravascular volume using esophageal Doppler on blood lactate
levels and organ dysfunction development in comparison with standard hemodynamic management
in multiple-trauma patients.

Methods

This was a randomized controlled trial. Multiple-trauma patients with blood loss of
more than 2,000 ml admitted to the intensive care unit (ICU) were randomly assigned
to the protocol group with esophageal Doppler monitoring and to the control group.
Fluid resuscitation in the Doppler group was guided for the first 12 hours of ICU
stay according to the protocol based on data obtained by esophageal Doppler, whereas
control patients were managed conventionally. Blood lactate levels and organ dysfunction
during ICU stay were evaluated.

Results

Eighty patients were randomly assigned to Doppler and 82 patients to control treatment.
The Doppler group received more intravenous colloid during the first 12 hours of ICU
stay (1,667 ± 426 ml versus 682 ± 322 ml; p < 0.0001), and blood lactate levels in the Doppler group were lower after 12 and 24
hours of treatment than in the control group (2.92 ± 0.54 mmol/l versus 3.23 ± 0.54
mmol/l [p = 0.0003] and 1.99 ± 0.44 mmol/l versus 2.37 ± 0.58 mmol/l [p < 0.0001], respectively). No difference in organ dysfunction between the groups was
found. Fewer patients in the Doppler group developed infectious complications (15
[18.8%] versus 28 [34.1%]; relative risk = 0.5491; 95% confidence interval = 0.3180
to 0.9482; p = 0.032). ICU stay in the Doppler group was reduced from a median of 8.5 days (interquartile
range [IQR] 6 to16) to 7 days (IQR 6 to 11) (p = 0.031), and hospital stay was decreased from a median of 17.5 days (IQR 11 to 29)
to 14 days (IQR 8.25 to 21) (p = 0.045). No significant difference in ICU and hospital mortalities between the groups
was found.

Conclusion

Optimization of intravascular volume using esophageal Doppler in multiple-trauma patients
is associated with a decrease of blood lactate levels, a lower incidence of infectious
complications, and a reduced duration of ICU and hospital stays.

Introduction

Post-traumatic hemorrhage in multiple-trauma patients leads to hypovolemia, in which
blood flow and consequently oxygen delivery to the tissues are decreased. Reduction
of oxygen delivery and oxygen consumption to below a critical level produces ischemic
metabolic insufficiency followed by increased generation of lactate [1-4]. Blood lactate levels are closely related to outcome in critically ill trauma patients
[4-9], and failure of serum lactate levels to reach normal values within a specific time
during critical illness could be even more closely related to survival than the initial
level [10-15]. According to a systematic Medicine/Cochrane Library literature search, blood lactate
level was shown to predict outcome in almost 3,000 multiple-trauma patients [4].

Fluid resuscitation of trauma patients has traditionally been guided by the normalization
of vital signs such as blood pressure, heart rate, and urine output. However, blood
pressure and heart rate remain relatively unchanged despite reduced blood flow to
certain tissues and hence they are insensitive indicators of hypovolemia and hypoperfusion
[14,16-18]. Occult hypoperfusion, defined as elevated blood lactate levels without signs of
clinical shock, was associated with increased morbidity and mortality, and early correction
is likely to improve the outcome [7,8,10,19].

The esophageal Doppler is a non-invasive technique for monitoring cardiac function
in intensive care unit (ICU) patients. The technique and clinical use were first described
in 1971 [20], subsequently refined by Singer and colleagues in 1989 [21], and recently have been successfully approved for optimizing fluid management perioperatively
and in intensive care patients [22-29]. Unfortunately, the Doppler probe is not readily tolerated by conscious patients,
restricting its use to patients who are sedated and ventilated. To our knowledge,
no prospective study has been performed to assess the efficacy of the esophageal Doppler
for optimization of fluid management in multiple-trauma patients in the immediate
postoperative period.

The aim of this study was to examine the effect of esophageal Doppler-guided fluid
management during the first 12 hours after ICU admission on blood lactate levels,
organ dysfunction development, infectious complications, and length of ICU and hospital
stays in comparison with standard hemodynamic management in multiple-trauma patients.

Materials and methods

This was a randomized, controlled, single-center study conducted in the interdisciplinary
ICU of a university teaching hospital. The study was approved by the Local Research
Ethics Committee of University Hospital in Plzeň (Czech Republic). Because the protocol
was approved and regarded as part of the routine practice and (due to the emergency
clause) informed consent by the patients or the family was not required, an independent
physician was designated to give the consent. However, subjects were informed at discharge
that they had participated in this clinical study.

Participants

Ventilated patients with multiple trauma and estimated blood loss of more than 2,000
ml admitted to the interdisciplinary ICU of our university teaching hospital from
2003 to 2005 were considered for inclusion in this study. We excluded patients younger
than 18 years old, patients with traumatic brain injury requiring treatment of intracranial
hypertension, and those with relative contraindications to the use of the esophageal
Doppler probe, such as orofacial and esophageal injury or other known oropharyngeal
and esophageal disease.

Protocol

Primary outcome measures were blood lactate levels after 12 and 24 hours after ICU
admission and organ dysfunction development during ICU stay. Secondary outcome measures
were duration of ICU and hospital stays and the incidence of infectious complications
during ICU stay.

Patients meeting inclusion criteria were randomly assigned to the protocol group (Doppler)
or the control group according to the assigned admission number generated by the admission
office of the university hospital (even: Doppler group, odd: control group). Randomization
of the patients was performed by a member of the research team at the time of ICU
admission. Data were analyzed on an intention-to-treat basis and included all patients
who were randomly assigned (Figure 1).

Patients with multiple trauma were initially examined and treated in the emergency
department of the university teaching hospital and after urgent surgery were admitted
to the ICU. The amount of blood loss in the pre-study period was estimated by an emergency
department physician and by an anesthesiologist taking care of the screened patient.
Neither of them was a member of the research team. At the time of ICU admission and
during the first 12 hours of ICU stay, all patients were mechanically ventilated (pressure-controlled
ventilation) and received adequate continuous analgosedation (fentanyl + midazolam)
to keep the Ramsay Scale score between 4 and 5 [30].

In the Doppler-guided fluid replacement group, the esophageal 7-mm probe was placed
into the lower esophagus through the mouth or nose to a depth of 35 to 40 cm from
the dental row within 30 minutes after ICU admission. The probe was rotated as needed
to obtain the best Doppler signal of blood flow in the midstream of the descending
aorta. Correct placement was assumed when reproducible, sharply defined waveforms
appeared on the screen of the monitor and crisp sound was heard through the loudspeaker.
The algorithm for fluid replacement during the first 12 hours after ICU admission
in the Doppler group was similar to that used by Sinclair and colleagues [23] (Figure 2). Corrected flow time (FTc) of less than 0.35 seconds was considered an indication
of possible hypovolemia. Patients were given an initial bolus of colloid (250 ml)
in a five minute period. If the stroke volume (SV) was either maintained or increased
after the fluid challenge and FTc remained below 0.35 seconds, the bolus of colloid
was repeated. If the FTc exceeded 0.35 seconds and the SV rose by more than 10%, the
fluid challenge was repeated. If the FTc exceeded 0.35 seconds and SV was unchanged
or rose by less than 10%, no further fluid was given until the FTc dropped below 0.35
seconds or SV fell by 10%. If the FTc rose above 0.40 seconds, no further fluid was
given until the FTc dropped below 0.35 seconds or SV fell by 10%. Esophageal Doppler
monitoring measurements were obtained using the Hemosonic 100 device (Arrow International,
Inc., Reading, PA, USA), which enables continuous measurement of descending thoracic
aorta blood velocity (Doppler transducer) and of aortic diameter (M-mode echo transducer).
The technical details and relative merits of this technique have been reviewed elsewhere
[31,32]. In the workplace where the study was implemented, the esophageal Doppler for hemodynamic
monitoring has been used routinely for several years and all members of the research
team were experienced in its use, and therefore measurement was performed by any of
the clinical study investigators. This fluid protocol started immediately after probe
placement and continued for 12 hours until the esophageal probe was removed. Following
fluid management in both groups was guided in the same way as in the control group.

Assessments

The following parameters were monitored during the study period: electrocardiograph,
pulse oximetry, invasive arterial pressure, CVP, urine output, and (in the Doppler
group) SV and FTc. Acute Physiology and Chronic Health Evaluation II (APACHE II) score
and Injury Severity Score (ISS) were calculated after admission to the ICU. Sequential
Organ Failure Assessment (SOFA) score was calculated daily, and the values at the
time of ICU admission and the highest SOFA during ICU stay were assessed. MAP and
CVP were evaluated at baseline and at the end of the 12-hour study period. Blood lactate
levels were assessed at baseline and 12 and 24 hours after ICU admission. The normal
value of blood lactate in our laboratory is less than 2.4 mmol/l. Rate and dose of
norepinephrine, volume of administered crystalloids and colloids, and blood and FFP
during the first 12 hours of the study period were assessed. Length of ICU and hospital
stays, ICU and hospital mortalities, and incidence of infectious complications during
ICU stay were evaluated. Diagnosis of infectious complications was established by
non-research staff in accordance with predefined criteria [33]. Patients were followed up to hospital discharge.

Statistical analysis

For the measure of primary outcome with reference to previous studies and our pilot
data [13,15,34,35], we calculated a study size of 75 patients in each group to demonstrate the decrease
of blood lactate levels by 0.6 mmol/l per 24 hours (standard deviation [SD] ± 1.3)
in the Doppler group in comparison with the control group. For the measure of secondary
outcome with reference to previous data [25], we calculated a sample size of 160 patients (80 in each group) by postulating a
reduction in mean ICU stay from nine days in the control group to seven days in the
protocol group (SD ± 4.5). Sample sizes were calculated for two-tailed tests allowing
for a type I error of 5% and a type II error of 20%. The Kolmogorov-Smirnov test was
used to check for normal distribution of data. Continuous normally distributed data
were tested with the t test, and not normally distributed data were tested with the Mann-Whitney U test. Categorical data were tested with the Fisher exact test. Data are presented
as means (SDs) where normally distributed and as medians (interquartile ranges) where
not normally distributed. Relative risk is presented with 95% confidence intervals
(CIs). A p value of less than 0.05 was considered statistically significant. Analysis was performed
with MedCalc® version 7.1.0.0 (Frank Schoonjans, MedCalc Software, Broekstraat 52, 9030 Mariakerke,
Belgium).

Results

A total of 162 patients were recruited between January 2004 and December 2005 (Figure
1). Eighty patients were randomly assigned to the Doppler group, and 82 patients to
the control group. The groups were well matched for age, gender, SOFA score at the
time of ICU admission, APACHE II score and ISS, and the type of injuries (Table 1). There were no differences between the Doppler and control groups in MAP, CVP, blood
lactate level, and frequency and dose of norepinephrine administration at baseline
(that is, at the time of ICU admission) (Table 2). After the 12-hour study period, blood lactate in Doppler group patients was lower
(2.92 ± 0.54 mmol/l versus 3.23 ± 0.56 mmol/l; p = 0.0003) as were the dose of norepinephrine (0.093 ± 0.035 μg/kg per minute versus
0.169 ± 0.068 μg/kg per minute; p = 0.0009) and the rate of norepinephrine (18 patients [23%] versus 33 patients [40%];
relative risk = 0.56, 95% CI = 0.34 to 0.91; p = 0.018). We found no difference between the Doppler and control groups in MAP, but
CVP in the Doppler group was higher (13.7 ± 1.8 mm Hg versus 12.1 ± 2.4 mm Hg; p < 0.0001). Patients in the Doppler group received a greater volume of colloid solutions
(1,667 ± 426 ml versus 682 ± 322 ml; p < 0.0001) but similar volumes of blood, FFP, and crystalloid solution (Table 3). The difference of lactate level between the Doppler and control groups changed
little after 24 hours of ICU stay (1.99 ± 0.44 mmol/l versus 2.37 ± 0.59 mmol/l; p < 0.0001). During ICU stay, no difference between the Doppler and control groups in
the highest SOFA score was found (10 [7 to 12.75] versus 11 [7 to 14]; p = 0.17), but in the Doppler group fewer patients developed infectious complications
(15 patients [18.8%] versus 28 patients [34.1%]; relative risk = 0.5491, 95% CI =
0.3180 to 0.9482; p = 0.032) (Table 4). The reduction of complications was associated with a reduction of median duration
of ICU stay (7 days [6 to 11] versus 8.5 days [6 to 16]; p = 0.031) as well as with a reduction of median duration of hospital stay (14 days
[8.25 to 21] versus 17.5 days [11 to 29]; p = 0.045) (Table 4). There was no significant difference in ICU and hospital mortalities (11 patients
[13.8%] versus 16 patients [19.5%] [p = 0.40] and 13 patients [16.3%] versus 18 patients [22%] [p = 0.43], respectively) (Table 4). There were no complications related to esophageal Doppler ultrasonography.

Table 1. Baseline characteristics of patients in the Doppler and control groups

Discussion

Esophageal Doppler-guided fluid management in multiple-trauma patients decreased blood
lactate levels, lowered the incidence of infectious complications, and reduced the
length of ICU and hospital stays. Occult tissue hypoperfusion in trauma patients is
relatively common and cannot be diagnosed and eliminated using traditional markers
and resuscitation endpoints (blood pressure, heart rate, and urine output). Scalea
and colleagues [16] found that up to 80% of critically ill patients who are normotensive and have adequate
urine output may remain in a state of compensated shock. One of most commonly used
markers in assessing occult tissue hypoperfusion in trauma patients is blood lactate.
Several studies have shown that normalization of blood lactate levels within 24 hours
of admission in hemodynamically stable trauma patients was associated with improved
survival, less frequent infection rate, and organ dysfunction development [7,8,10-12]. Persistent elevated lactate levels 24 hours after admission significantly correlated
with mortality [13]. Limited prospective data are available, but these indicate that rapid normalization
of increased blood lactate levels is an important therapeutic goal in critically ill
patients [19]. Adequate fluid resuscitation to increase cardiac output has been found to improve
tissue oxygen delivery in patients with tissue hypoxia and remains the mainstay of
therapy in these circumstances [36]. Esophageal Doppler flowmetry used to maximize intraoperative SV by repeated fluid
challenges was associated with improved outcome and reductions in length of hospital
stay after cardiac, orthopedic, or abdominal surgery [22-25,28]. Our data are in agreement with other studies [19,26,36] and support the statement that some beneficial effects might still be achieved from
optimization of circulatory status in the immediate postoperative period.

Although decreased blood lactate levels in Doppler group patients during the first
12 and 24 hours of ICU stay indicate improved tissue perfusion and oxygenation, surprisingly
we did not prove a significant difference between the Doppler and control groups in
organ failure development during ICU stay. Presumably, the difference in tissue oxygen
delivery in both groups was not significant enough to induce organ-function changes
measurable by SOFA score. With reference to the 'golden hour' and the 'silver day'
of trauma resuscitation [10,37], a partial explanation for this finding can be that despite the higher blood lactate
levels in control group patients, oxygen delivery in both groups was sufficient to
achieve normal lactate levels within 24 hours of ICU stay. However, other factors
that could help to explain the uniformity in levels of organ dysfunction and mortality
between the protocol and control groups (that is, amount of time elapsed between the
injury and emergency department admission, duration of surgery, and amount of blood
transfused before ICU admission) were not analyzed.

A relationship between the rapid normalization of blood lactate level and the lower
rate of infectious complications in trauma patients was clearly demonstrated [7,8,10,36]. The blood lactate level in the control group after 12 and 24 hours of study was
higher than in the Doppler group, and even though the blood lactate level after 24
hours of ICU stay in both groups reached the normal range, more patients in the control
group developed infectious complications during ICU stay. Clinical studies support
the notion that adequate fluid resuscitation may improve tissue oxygen tension and
decrease the rate of complications [22,38]. Other studies have demonstrated that inadequate tissue perfusion measured with gastric
tonometry is associated with adverse perioperative outcome [39,40]. Possibly, better tissue oxygenation results in improved tissue healing and decreased
infection rate.

The use of esophageal Doppler for hemodynamic optimization based on administering
fluids to achieve maximal left ventricular SV was associated with important reductions
of ICU or hospital stay [22-26]. In the present study, esophageal Doppler-guided fluid management was associated
with a 1.5-day median reduction in ICU stay and a 3.5-day median decrease in hospital
stay. This suggests that optimization of circulatory status may also have financial
implications and reduce the cost of care for multiple-trauma patients.

In a meta-analysis of hemodynamic optimization studies, Poeze and coworkers [41] showed that the use of strategies to optimize the hemodynamic condition perioperatively
and during trauma significantly reduced mortality. In the present study, there was
no statistical difference in ICU and hospital mortalities between the groups, and
the study was not powered to show any difference in mortality. This would have required
more than 700 patients.

There are some potential weaknesses in the design of our trial. It was of relatively
small size, was not blinded, and was conducted in only one center. All patients in
the control group received intravenous resuscitation guided by CVP measurement in
order to keep CVP between 12 and 15 mmHg. However, because no reliable correlation
between intravascular volume and absolute CVP measurement has been established, rather
than apply an absolute target for CVP, dynamic changes of CVP to fluid challenge would
likely provide a more reliable guide to fluid requirements [24,36]. Recruitment of patients was possible only when a member of the research team was
available to administer the 12-hour study protocol. During the trial period, 539 multiple-trauma
patients were admitted to the ICU and mortality was 22.4% (including deaths within
24 hours after ICU admission).

The application of the 12-hour study protocol in the Doppler group was time-consuming
and would not have been feasible without the close cooperation of the nursing staff.
The continuous presence of a clinician at bedside for a 12-hour period is not realistic
and thus the fluid challenge according to the Doppler-guided protocol was given partly
by trained nursing staff. Whenever the quality of the Doppler signal was altered (due
mostly to a change of probe position resulting from nurse or patient movement), a
member of the research team was called and the probe was restored to the proper position.
In spite of adequate sedation, it was difficult to keep the Doppler probe in the right
position for 12 hours without frequent adjustments. We suppose that the use of other
relatively non-invasive devices that measure SV and cardiac output (for example, cardiac
output measurement using partial carbon dioxide rebreathing, thoracic impedance, and
technologies using arterial pressure waveform analysis) may be less demanding for
postoperative fluid and hemodynamic optimization. Moreover, these methods do not require
deep sedation, can be used for longer periods, and do not discriminate patients who
are not suitable for esophageal Doppler monitoring.

Conclusion

Optimization of intravascular volume using esophageal Doppler in multiple-trauma patients
is associated with a decrease of blood lactate levels, a lower incidence of infectious
complications, and a reduced duration of ICU and hospital stays. A large multicenter
study should be performed to validate these findings and to demonstrate an effect
on mortality.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

IC and RP were responsible for study design and data analysis. All authors were responsible
for administering the protocol, were involved in drafting the manuscript and approved
the final version, and have full access to the data and take full responsibility for
the integrity of the data.

Acknowledgements

The study was supported by a research grant (IGA MZ CR ND/7712-3) and by the Czech
Ministry of Education (project MSM0021620819).